Defective macrophage handling of Escherichia coli in Crohn's disease.

BACKGROUND AND AIM: Escherichia coli can be isolated from lamina propria macrophages in Crohn's disease (CD), and their intramacrophage persistence may provide a stimulus for inflammation. To further determine the contributions of macrophage dysfunction and E. coli pathogenicity to this, we aimed to compare in vitro functioning of macrophages from patients with CD and healthy controls (HC) in response to infection with CD-derived adherent-invasive E. coli (AIEC) and less pathogenic E. coli strains. METHODS: Monocyte-derived macrophages were cultured from patients with CD and HC. Intramacrophage survival of E. coli strains (CD-derived adherent-invasive [AI] and non-AI strains and laboratory strain K-12) was compared. Macrophage cytokine release (tumor necrosis factor alpha [TNFα], interleukin [IL]-23, IL-8 and IL-10) and monocyte phagoctyosis and respiratory burst function were measured after E. coli infection. For CD patients, laboratory data were correlated with clinical phenotype, use of immunomodulation, and CD risk alleles (NOD2, IL-23R, ATG16L1 and IRGM). RESULTS: Attenuated TNFα and IL-23 release from CD macrophages was found after infection with all E. coli strains. There was prolonged survival of CD-derived AIEC, CD-derived non-AIEC and E. coli K-12 in macrophages from CD patients compared to within those from HC. No abnormality of monocyte phagocytosis or respiratory burst function was detected in CD. Macrophage dysfunction in CD was not influenced by phenotype, use of immunomodulation or genotype. CONCLUSIONS: CD macrophage responses to infection with E. coli are deficient, regardless of clinical phenotype, CD genotype or E. coli pathogenicity. This suggests host immunodeficiency is an important contributor to intramacrophage E. coli persistence in CD.

Dietary intervention for oral allergy syndrome as a treatment in orofacial granulomatosis: a new approach?

BACKGROUND: Orofacial granulomatosis (OFG) is a chronic granulomatous condition of the mouth, face and lips. Recent work demonstrates a high rate of atopy and silver birch sensitisation from skin prick testing (SPT). Oral allergy syndrome (OAS) is an acute oro-pharyngeal IgE mediated reaction, triggered by foods that cross react with pollens, most commonly silver birch. The aim of this study was to determine if patients with OFG and positive SPT to common OAS associated pollens responded to avoidance of cross reactive foods. METHODS: Patients with OFG and positive SPT to silver birch, grass, mugwort, ragweed and latex were required to avoid cross reacting foods, for 6 weeks and, in those who responded, for a total of 12 weeks. All had standardized oral examinations and were given severity scores (SS) at each appointment. RESULTS: Twenty two of 47 (47%) patients had one or more positive SPT and 13/22 completed 6 weeks on the diet. No difference was seen in SS between weeks 0 (14.62 ± 11.16) and 6 (13.31 ± 10.33; P = 0.656). Six of 14 (43%) had significantly improved SS (week 0; 19.17 ± 12.95, week 6; 10.83 ± 4.99, P = 0.027). Five completed 12 weeks and no further improvement was seen (week 6; 11 ± 5.57, week 12; 10.4 ± 9.94; P = 0.068). Two patients required no further treatments. CONCLUSIONS: On an intention to treat basis, only 2/14 patients improved and required no further intervention. Whilst this diet cannot be recommended routinely, the improvement seen in some patients raises questions about the role of OAS in patients with OFG.

Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome.

BACKGROUND: There is increasing evidence to support a role for the gastrointestinal microbiota in the etiology of irritable bowel syndrome (IBS). Given the evidence of an inflammatory component to IBS, the mucosa-associated microbiota potentially play a key role in its pathogenesis. The objectives were to compare the mucosa-associated microbiota between patients with diarrhea predominant IBS (IBS-D), constipation predominant IBS (IBS-C) and controls using fluorescent in situ hybridization and to correlate specific bacteria groups with individual IBS symptoms. METHODS: Forty-seven patients with IBS (27 IBS-D and 20 IBS-C) and 26 healthy controls were recruited to the study. Snap-frozen rectal biopsies were taken at colonoscopy and bacterial quantification performed by hybridizing frozen sections with bacterial-group specific oligonucleotide probes. KEY RESULTS: Patients with IBS had significantly greater numbers of total mucosa-associated bacteria per mm of rectal epithelium than controls [median 218 (IQR - 209) vs 128 (121) P = 0.007], and this was chiefly comprised of bacteroides IBS [69 (67) vs 14 (41) P = 0.001] and Eubacterium rectale-Clostridium coccoides [52 (58) vs 25 (35) P = 0.03]. Analysis of IBS sub-groups demonstrated that bifidobacteria were lower in the IBS-D group than in the IBS-C group and controls [24 (32) vs 54 (88) vs 32 (35) P = 0.011]. Finally, amongst patients with IBS, the maximum number of stools per day negatively correlated with the number of mucosa-associated bifidobacteria (P < 0.001) and lactobacilli (P = 0.002). CONCLUSIONS & INFERENCES: The mucosa-associated microbiota in patients with IBS is significantly different from healthy controls with increases in bacteroides and clostridia and a reduction in bifidobacteria in patients with IBS-D.

Glucocorticoids as a novel approach to the treatment of disabling side effects of sodium stibogluconate.

WHAT IS KNOWN AND OBJECTIVE: Intravenous sodium stibogluconate (SbV) is the mainstay of treatment for mucocutaneous leishmaniasis. Incidence of this disease is increasing in the UK, partly because of returning military personnel. SbV has a side effect profile that requires treatment interruption in up to 28% of patients. Side effects can be unpleasant and - in the case of QTc prolongation - dangerous. CASE SUMMARY: A volunteer medical worker returning from Guatemala was diagnosed with mucocutaneous leishmaniasis. Because of previous renal problems, NSAIDs were contraindicated. Severe side effects of myalgia and arthralgia would have necessitated a treatment interruption, but a trial of prednisolone gave excellent symptomatic relief. The patient's QTc, amylase and C-reactive protein also fell following initiation of steroid treatment. The SbV treatment course was completed successfully. WHAT IS NEW AND CONCLUSION: This is the first reported case of the dangerous and disabling side effects of SbV being treated very effectively with glucocorticoids. Of note is the normalization of the apparently sodium stibogluconate-induced prolongation of the QTc interval. Further investigation into this potential beneficial effect is warranted.

Phenytoin toxicity: an easily missed cause of cerebellar syndrome.

We present a series of cases of phenytoin toxicity where the diagnosis was initially missed. These patients all suffered unnecessary morbidity or investigations. The side-effects and unusual pharmacokinetics of phenytoin are discussed, as well as the array of potential drug interactions. We remind clinicians that phenytoin toxicity can easily mimic a cerebellar lesion or alcohol intoxication, and suggest that in accordance with National Institute for Clinical Excellence (NICE) guidelines phenytoin should no longer be used as a first-line treatment for epilepsy.

Post-influenza vaccine chronic inflammatory demyelinating polyneuropathy.

We present a case of chronic inflammatory demyelinating polyneuropathy occurring subsequent to influenza vaccination in a 74-year-old gentleman with no previous neurological history.

Molecular characterization of the bacteria adherent to human colorectal mucosa.

AIMS: To study large intestinal mucosal bacterial communities by Denaturing Gradient Gel Electrophoresis (DGGE) profiling and sequencing of 16S rRNA gene polymerase chain reaction (PCR) products amplified from DNA extracted from colorectal biopsies taken from healthy individuals. The specific aims were to determine how similar the mucosa-associated bacterial communities are within and between individuals and also to characterize the phylogenetic origin of isolated DGGE bands. METHODS AND RESULTS: Human colorectal biopsies were taken at routine colonoscopy from 33 patients with normal looking mucosa. The DNA was extracted directly from single biopsies and the bacterial 16S rDNA PCR amplified. The PCR products were profiled using DGGE to generate a fingerprint of the dominant members of the bacterial community associated with the biopsy. The reproducibility of this method was high (>98%). Washed and unwashed biopsies gave similar DGGE banding patterns (Median Similarity Coefficient - MSC 96%, InterQuartile Range - IQR 3.0%, n = 5). Adjacent biopsies sampled from the same patient using different forceps gave similar DGGE profiles (MSC 94%, n = 2). Two colorectal biopsies sampled at locations 2-5 cm apart, from each of 18 patients, resulted in very similar profiles (MSC 100%, IQR 2.8%). Biopsies sampled from different locations within the large intestine of the same patient also gave similar DGGE profiles (MSC 98% IQR 3.3%n = 6). Although all patients (n = 33) gave different DGGE profiles, some similarity (c. 34%) was observed between profiles obtained from 15 patients arbitrarily selected. 35 DGGE bands were excised and sequenced. Many were found to be most closely related to uncultured bacterial sequence entries in the Genbank database. Others belonged to typical gut bacterial genera including Bacteroides, Ruminococcus, Faecalibacterium and Clostridium. CONCLUSIONS: Bacterial communities adherent to colorectal mucosa within a normal patient show little variation; in contrast, mucosal bacterial communities sampled from different patients with normal colorectal mucosa show a high degree of variation. SIGNIFICANCE AND IMPACT OF THE STUDY: This research demonstrates that DGGE profiling of 16S rRNA gene PCR products amplified from DNA extracted directly from mucosal samples offers fresh insight into the bacterial communities that are adherent to colorectal mucosa. These findings are important with respect to further studies on the gastrointestinal tract in health and disease.

Mizolastine therapy also has an effect on nasal blockade in perennial allergic rhinoconjunctivitis. RIPERAN Study Group.

BACKGROUND: Mizolastine is a new, nonsedating antihistamine with additional anti-inflammatory properties, providing relief in allergic rhinitis and urticaria. The aim of this study was to determine the efficacy and safety of 10 mg o.d. mizolastine given to patients with perennial allergic rhinoconjunctivitis. METHODS: This double-blind, placebo-controlled study involved 257 patients suffering from the disease for more than 10 years. They were allocated, after a 1-week placebo run-in, to receive mizolastine (n = 133) or placebo (n = 124) for 4 weeks. RESULTS: Mizolastine-treated patients showed significantly greater alleviation of nasal symptoms, with a mean decrease of 36% compared with pretreatment score, compared to a mean decrease of 10% in placebo patients (P < 0.001). Nasal blockade responded favorably to mizolastine compared to placebo and was associated with a significant reduction in rhinoscopy findings (P = 0.030). Likewise, the mean ocular symptom score decreased 40% in mizolastine-treated patients compared to 7% in the placebo group (P < 0.003). The safety profile of mizolastine was satisfactory and similar to that of placebo. CONCLUSIONS: In patients suffering from perennial allergic rhinoconjunctivitis, mizolastine is a safe and potent treatment. Mizolastine's pronounced effect on nasal blockade could possibly be linked to its anti-inflammatory properties.

Brain MR in chronic fatigue syndrome.

PURPOSE: To determine the prevalence of MR white matter abnormalities in patients with chronic fatigue syndrome (CFS). METHODS: Brain MR studies of 43 patients (29 women and 14 men, 22 to 78 years old) with a clinical diagnosis of CFS (n = 15), CFS with associated depression (n = 14), and CFS with associated other psychiatric disorders, namely, anxiety and somatization disorder (n = 14), were compared with brain MR studies in 43 age- and sex-matched control subjects. RESULTS: MR findings were abnormal in 13 (32%) of the patients in the study group (ages 34 to 78 years) and in 12 (28%) of the control subjects (ages 26 to 73 years). One patient with CFS had multiple areas of demyelination in the supratentorial periventricular white matter. Another patient with CFS and associated depression had a single focus of probable demyelination in the supratentorial periventricular white matter. In four patients with CFS (ages 34 to 48 years) MR abnormalities consisted of one or several punctate hyperintense foci in the corona radiata, centrum ovale, and frontal white matter. The remaining seven patients (ages 50 to 78 years) had frontoparietal subcortical white matter foci of high T2 signal. The prevalence of white matter hyperintensities was not different between the patients and the control subjects. CONCLUSIONS: Our findings suggest that no MR pattern of white matter abnormalities is specific to CFS.

Food sensitivity and rheumatoid arthritis.

The majority of double-blind placebo-controlled trials have shown that 30-40% of rheumatoid arthritis (RA) patients can improve substantially by using an elimination diet to identify foods that precipitate symptoms and the avoiding of these foods. Some such patients have discontinued drug treatment and remained well for 12 years or more. Prior to the elimination diet, most patients had not recognised diet as a trigger for their symptoms, because the offending foods were eaten daily. (Foods eaten infrequently can also provoke sensitivity, resulting in episodic arthritis.) Additionally, many RA patients are sensitive to several foods, making a rigorous elimination diet essential for diagnosis. The pattern of response to an elimination diet (30-40% of RA patients respond well; response occurs within 10-21 days; benefits are maintained if offending foods are avoided) is markedly different from the pattern of response to a fast (almost all RA patients respond well; response occurs within 3-5 days; benefits are lost rapidly when a normal diet is resumed). Clearly fasting and the elimination diet have different therapeutic mechanisms. The effect of fasting may be mediated by the absence of dietary fat, leading to a shortage of pro-inflammatory prostaglandins and leukotrienes. The mechanism by which food sensitivity is involved in rheumatoid arthritis remains unknown, but weight loss is definitely not responsible for the improvement seen on an elimination diet. Some evidence implicates the gut flora. Food-sensitive RA patients may also show changes in immune parameters during an elimination diet, but no consistent universal change has yet been found.

Allergen-specific low-dose immunotherapy in perennial allergic rhinitis: a double-blind placebo-controlled crossover study.

In a double-blind placebo-controlled crossover study, 36 adults with perennial allergic rhinitis were treated with daily subcutaneous injections of inhalant allergens, the doses of which had been predetermined by intradermal testing. The dose chosen for each allergen was the maximum intradermally tolerated dose (MITD) of that allergen, defined as 0.05 ml of the strongest concentration in a 1:5 dilution series which did not produce a positive wheal. Of the 27 who expressed a preference, 21 (78%) preferred the active preparation and six (22%) the placebo (p = 0.006). Significant symptom relief was apparent on an analysis of total rhinitis symptom scores (p = 0.006), nasal blockage (p = 0.02), nasal discharge (p = 0.006), postnasal drip (p = 0.02) and anosmia (p = 0.02). These results support the validity of allergen-specific low-dose immunotherapy using the MITD.

Razi's report about seasonal allergic rhinitis (hay fever) from the 10th century AD.

Seasonal allergic rhinitis (hay fever) is considered a disease of the postindustrial revolution era. Clinical reports of patients are readily available from the 19th century starting with John Bostock's description of his own summer symptoms. Also patients with "rose catarrh' are described in the 16th and 17th century. Although asthma is well described by Maimonides, clear descriptions of diagnosis, prevention and treatment of hay fever are rare in the first millennium. This report by Razi (prior to 925 AD) is perhaps the earliest such report yet. It is contained in a compendium written by Ibn Sharabeyun ben Ibrahim in the 13th or 14th century AD. The volume also contains work by Avicenna (Abo Ali-Sina; a friend of Razi) and other contemporary writers. Some of the treatments suggested in this early report may not be so acceptable to modern sufferers.

Efficacy of mizolastine, a new antihistamine, compared with placebo in the treatment of chronic idiopathic urticaria.

A two-centre, double-blind, randomized, placebo (P)-controlled, parallel-group study was conducted in the UK to examine the efficacy and safety of mizolastine (M), a new H1-receptor antagonist, as a once-daily 10-mg dose in chronic idiopathic urticaria. Fifty-six outpatients (M: n = 28; P: n = 28) with a mean age of 38 +/- 15 years, a duration of disease of more than 3 years, and symptoms of urticaria at least twice a week in the absence of treatment were recruited. After a single-blind placebo run-in period, patients were allocated to one of two treatment groups and were evaluated after 7 and 28 days. The main characteristics (age, duration of disease, number of urticarial episodes, and total score) of the two groups were comparable at inclusion. Mizolastine was shown to improve the urticaria symptoms: at the end of the study, mizolastine produced a significantly greater decrease in the global symptom score comprising itch, wheals, and erythema (M: 2.1 +/- 2.1 vs P: 0.4 +/- 2.0; P = 0.002). The patient-rated global discomfort from symptoms measured by visual analog scale was significantly improved with mizolastine (M: 31.4 +/- 36.7) compared to placebo (P: 5.4 +/- 27.6; P = 0.003), with respectively more M responders (74.1%) than P responders (28.6%, P = 0.001), a responder being a patient with a > or = 50% decrease in VAS. Premature dropouts due to lack of efficacy and loss to follow-up mainly occurred at the first evaluation (day 7) and were more often observed in patients in the placebo group (n = 17) than in the mizolastine group (n = 8) (P = 0.031). No serious adverse events were recorded. Somnolence was reported in two mizolastine patients, one of whom discontinued the study. Thus, mizolastine may be considered a new treatment option for the symptoms of chronic urticaria.

Association of immunological changes with clinical efficacy in atopic eczema patients treated with traditional Chinese herbal therapy (Zemaphyte).

The efficacy of the Chinese herbal therapy (Zemaphyte) has been well established as a treatment for atopic eczema (AE) in clinical trials. The purpose of this study was to probe the immunological changes that occurred when patients were treated with the herbs for a period of 8 weeks. This treatment decreased serum IgE complexes (p less than 0.05) but did not affect total serum IgE or CD23 expression on peripheral blood monocytes. Peripheral blood mononuclear cells from patients before and after treatment were cultured overnight with interleukin 4 and the ability of this cytokine to induce CD23 on monocytes from treated patients was found to be significantly diminished (p less than 0.01). Soluble interleukin 2 receptor and soluble vascular cell adhesion molecule were both raised in the serum of AE patients compared to control individuals. Both these parameters were decreased following treatment (p less than 0.05). All these changes coincided with improvement in erythema and surface damage scores. There was no alteration in soluble intracellular adhesion molecule or soluble CD23. The results of these investigations would suggest that this herbal treatment has the ability to target various immunological parameters which may be involved in the pathogenesis of AE.